7. Project Summary/Abstract Reward deficits in psychiatric disorders are unresponsive to currently available medications and contribute significantly to poor functional outcomes. A deeper understanding of the neural mechanisms underlying reward processing is necessary to identify novel therapeutic targets to improve reward function in psychiatric disorders. Here, we will use fiber photometry, optogenetics, and computational modeling with cross-species translational behavioral tasks in rats to understand the role of glutamate, dopamine, and serotonin circuit activity in regulating reward function. Reward processing includes feedback-driven decision-making and goal- directed action, enabling individuals to integrate reward-feedback, detect violations in expected and actual outcomes, and to appropriately guide reward-related decisions. The orbitofrontal cortex (OFC), the ventral tegmental area (VTA), and the dorsal raphe nucleus (DRN) are brain regions implicated in signaling changes in expected reward outcomes. Activation of the OFC suppresses VTA dopamine (DA) activity and OFC activity increases DRN serotonin (5-HT) cell activity. However, it is unknown whether OFC modulation of VTA or DRN activity alters DA or 5-HT transmission within the OFC, or whether this modulation regulates feedback-driven decision-making or goal-directed behavior. The Probabilistic Reversal Learning and/or 2-step reinforcement learning tasks can be used to evaluate these reward processes. As performance in these tasks is impaired in several psychiatric disorders, identifying the mechanisms regulating optimal task performance may identify potential therapeutic strategies to improve reward function in psychiatry. The aims of this R21 application are to: (1) identify how the dynamics of reciprocal OFC-VTA and OFC-DRN circuit activity changes during reward learning and respond to different types of response feedback, (2) directly manipulate OFC glutamate terminals within the VTA or DRN to determine whether the OFC directly modulates DA or 5H-T transmission within the OFC, and (3) determine the consequence of such modulation on feedback-driven decision-making and goal- directed behavior. This project will use transgenic rats expressing cre-recombinase in DAergic cells or 5- HTergic cells, dual-color calcium imaging, and combined fiber photometry/optogenetics to determine the neural mechanisms regulating performance in the PRL and 2-step tasks. Behavioral data will be fitted to computational models and alterations in calcium signal will be correlated with behavioral outcomes to identify how neural activity regulates choice behavior. Findings generated from this project will lay the groundwork for a future R01 application that will investigate the potential of modulating glutamate, DA, and/or 5-HT transmission to improve reward function in experimental systems of psychiatric disorders. Such research, bringing a new circuit-based level of understanding, will identify novel therapeutic strategies to improve feedback-driven decision-making and goal-directed behavior in psychiatric disorders.